In Situ Reprogramming of Senescent Microenvironment via Augmentation of Endogenous Senolytic Actions for Advanced Atherosclerosis Management.

Zhiyue Wang, Xing Chen, Yutong Xu, Xiang Guo, Xingji Liu, Ximei Dai, Jiaqi Lu, Jianchen Qi, Tao Zheng, Linlin Zhang, Long Ma, Sheng Wang, Guifen Yang, Guangming Lu, Feng Wang, Qing Zhou, Jie Sheng, Longjiang Zhang

Department of Radiology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu 210008, China.Department of Radiology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu 210008, China. · pubmed

Paper

Abstract

Advanced atherosclerosis (AS) poses substantial residual risk of life-threatening cardiovascular disease, even with optimized lipid-lowering therapies. Histopathological evaluation of clinically obtained specimens revealed that advanced plaques developed a distinct senescent microenvironment compared to early stage lesions, and senescent foam cells (FCs) are the culprits in creating the pathological microenvironment via initiating senescence-propagating crosstalk with multiple vascular cells. Herein, we synthesized a zeolitic imidazolate framework-8 (ZIF-8)-based nanomedicine denoted as L-pKNZ. Unlike conventional senolytic agents that primarily induce cellular apoptosis, L-pKNZ activates FC autophagy and enhances macrophage efferocytosis. This strategy established an endogenous senolytic system to relieve FC overload while simultaneously reprogramming the senescent microenvironment. Results from multiomics analysis aligned with outcomes from in vitro/in vivo experiments, all in favor of vascular rejuvenation and AS amelioration. Critically, we successfully radiolabeled L-pKNZs with the radionuclide

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Research summary

The paper claims that the synthesized nanomedicine L-pKNZ can reprogram the senescent microenvironment in advanced atherosclerosis by enhancing autophagy and efferocytosis. This research addresses the underlying mechanisms of cellular senescence, which is a key factor in aging and age-related diseases, thus contributing to longevity research.

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